Background

In 1963, Joseph Murray and colleagues reported the first known pregnancy after kidney transplantation . The recipient received a kidney from her identical twin sister; therefore, immunosuppression was not an issue. The recipient delivered a healthy baby boy at 40 weeks via cesarean section. Since that first report, there have been many advances in immunosuppression and thousands of solid-organ transplant recipients worldwide have had successful pregnancies after transplantation .

From the 1960s to the 1980s, immunosuppressive regimens for transplantation were limited to azathioprine and prednisone. Then, the era of calcineurin inhibitors was ushered in with cyclosporine, used in combination with the prior medications. In the early 1990s, a second calcineurin inhibitor, tacrolimus, was introduced. Tacrolimus and cyclosporine have the same intracellular mechanism, and are not used together but are used in combination with other immunosuppressives. In the mid-1990s, the mycophenolate drugs were introduced and largely replaced azathioprine . Sirolimus, an antiproliferative agent in its own class, appeared in the late 1990s, and unlike calcineurin inhibitors, is not nephrotoxic . In an effort to improve both efficacy and decrease side effects, the different immunosuppressive medications are used in various combinations. The most common posttransplantation regimen currently prescribed is tacrolimus plus mycophenolate with or without prednisone.

Immunosuppressive regimens are classified into three general categories: (1) induction agents, used in the first week posttransplant, include biological agents such as antilymphocyte sera (polyclonal or monoclonal antibodies) or interleukin-2 (IL-2) receptor blockers; (2) antirejection agents , used to treat rejection episodes, include high-dosage, short-term treatments such as corticosteroids or antilymphocyte sera; and (3) maintenance regimens, started soon after transplantation to provide long-term immunosuppression. Maintenance regimens are initiated at higher dosages and are lowered through the posttransplant first year. Maintenance immunosuppressive therapy will be taken by almost all pregnant solid-organ transplant recipients.

In general, it is recommended that women refrain from taking medications during pregnancy unless it is necessary. As most transplant recipients must take immunosuppressive medications to preserve their transplant function, the National Transplantation Pregnancy Registry (NTPR) was established in the United States in 1991 to study the safety of these medications during pregnancies in transplant female recipients and in pregnancies fathered by transplant recipients. The NTPR is an active registry that continuously collects and analyzes data from transplant recipients, their health-care providers, and medical records review. The different types of solid-organ recipients and the number of pregnancies in the NTPR as of December 2013 are summarized in Table 1 . A unique feature of the registry is long-term follow-up; early participants have been followed up for over 20 years and some are now grandparents. The NTPR is a multicenter condition-based registry, and as such, it can address evolving concerns in the transplant community and adapts to the introduction of new immunosuppressive therapies. Case and center reports, meta-analyses, and registry reports are crucial to the understanding of the effect of these therapies during pregnancy on the recipient, their transplant, and the developing child.

Immunosuppressive agents

This section reviews the mechanisms of action and teratogenic risk of current immunosuppression and presents pregnancy outcome data associated with different immunosuppressive agents.

Teratogenic risk can be measured in various ways. The US Food and Drug Administration (FDA) classifies the pregnancy safety of medications by category as follows: Category A – if adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters); Category B – if animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; Category C – if animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; Category D – if there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; Category X – if studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigational or post marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit . Most immunosuppressive agents fall into Category C where the risks and benefits have to be considered. In 2008, the FDA proposed a change to their classification system, which is still in review, to reflect a more comprehensive risk–benefit ratio to better aid health-care providers counsel patients . Commonly used transplant immunosuppressive agents and their related dosing and pregnancy information are listed in Table 2 .

According to the Center for Disease Control (CDC), approximately 3–5% of the children in the United States are born with a major structural or genetic birth defect . A principle of teratology is that the susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which it interacts with the environment . Thus, in the transplant population, where there are multiple etiologies of the original organ failure and multiple medication exposures, susceptibility will vary among patients.

Immunosuppressive agents

This section reviews the mechanisms of action and teratogenic risk of current immunosuppression and presents pregnancy outcome data associated with different immunosuppressive agents.

Teratogenic risk can be measured in various ways. The US Food and Drug Administration (FDA) classifies the pregnancy safety of medications by category as follows: Category A – if adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters); Category B – if animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women; Category C – if animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; Category D – if there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks; Category X – if studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigational or post marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit . Most immunosuppressive agents fall into Category C where the risks and benefits have to be considered. In 2008, the FDA proposed a change to their classification system, which is still in review, to reflect a more comprehensive risk–benefit ratio to better aid health-care providers counsel patients . Commonly used transplant immunosuppressive agents and their related dosing and pregnancy information are listed in Table 2 .

According to the Center for Disease Control (CDC), approximately 3–5% of the children in the United States are born with a major structural or genetic birth defect . A principle of teratology is that the susceptibility to teratogenesis depends on the genotype of the conceptus and the manner in which it interacts with the environment . Thus, in the transplant population, where there are multiple etiologies of the original organ failure and multiple medication exposures, susceptibility will vary among patients.

Corticosteroids (Category C)

Corticosteroids have broad anti-inflammatory and immunosuppressive effects and continue to be a component of many immunosuppressive regimens. One extensive survey of the literature analyzed 468 cortisone-exposed gravidas and noted an overall fetal malformation rate of 3.5%, no greater than that found in the general population, although the incidence of oral cleft was slightly greater . In a meta-analysis of women with oral corticosteroids administered during the first trimester, again there was no overall higher rate of major anomalies, but there was a 3.4-fold increase in the risk of oral clefts, which is similar to outcomes of animal reproduction studies . When data from six studies were pooled and analyzed by Oren et al., no increase in oral clefts was seen . The authors concluded that the potentially serious implications of discontinuing or initiating corticosteroids during pregnancy must be weighed against the increased risk of oral clefts. A recent analysis of data from nationwide Danish registries did not show a risk of orofacial clefts associated with corticosteroid use . Each of these human studies were affected by biases, including route of exposure, concomitant medication exposure, and timing of reports; overall, when used in therapeutic dosages, prednisone poses a minimal risk to the developing fetus .

Azathioprine (Category D)

Azathioprine is an inhibitor of purine metabolism and, following absorption, is rapidly converted in the liver into a number of metabolites. Its active metabolite, 6-mercaptopurine, has been found in cord blood . The teratogenicity of azathioprine was associated with embryonic resorption and/or fetal anomalies in animal studies when administered at doses similar to the human dose and, thus, was listed as a Category D agent . However, clinical data have not supported the results of the animal studies. Preterm delivery and fetal growth restriction have been noted, but without any predominant structural malformation pattern .

Before the introduction of cyclosporine, azathioprine represented the primary immunosuppressive agent. Doses ranged up to 2.5 mg/kg once daily in combination with prednisone. Azathioprine is now used as an adjunctive drug with cyclosporine or tacrolimus and dosages have decreased (0.5–1 mg/kg/d). As more effective drugs have been developed, the use of azathioprine in transplantation has greatly fallen.

Cyclosporine (Category C)

In the 1980s, cyclosporine was introduced and quickly became the primary immunosuppressant of choice due to lower rejections rates and higher graft survival rates. This cyclic-11 amino acid peptide inhibits calcineurin, blocking the transcription of cytokine genes necessary for T-cell activation and proliferation. Cyclosporine’s usual dosage range is 2–10mg/kg/d in two divided doses and in contrast to corticosteroids and azathioprine, dosing is adjusted by measuring trough blood levels . Common side effects include nephrotoxicity, hypertension, tremor, hypertrichosis, and hyperlipidemia. Fetal toxicities and abnormalities in animal studies were noted at dosages higher than those in clinical use . Early reports raised concerns about the safety of cyclosporine use during pregnancy . Other reviews of cyclosporine use during pregnancy for non-transplant indications did not reveal a pattern of malformation and/or problems in the newborn . Clinical data have not demonstrated an increased incidence of congenital malformations, and although there is a moderate risk of fetal growth restriction, the consensus is that the teratogenic risk is minimal .

Tacrolimus (Category C)

Tacrolimus, a macrolide antibiotic calcineurin inhibitor, is more potent than cyclosporine. The usual oral dosage range is 0.05–0.2 mg/kg/d in two divided doses. Common side effects include nephrotoxicity, neurotoxicity, and diabetes mellitus . As with cyclosporine, in animal studies tacrolimus revealed fetal resorptions at doses higher than those in clinical use, whereas in a lower dosage group (0.16 mg/kg/day), surviving fetuses appeared no different from controls . Based on data from the NTPR and other large cohorts, there has not been an increase in the incidence of malformations or any recurrent pattern of malformations among the offspring exposed to tacrolimus .

Mycophenolic acid products (Category D)

Mycophenolate mofetil (MMF) is a prodrug which undergoes hepatic ester hydrolysis to form the active metabolite mycophenolic acid (MPA) products. MPA is a reversible inhibitor of inosine monophosphate dehydrogenase, which blocks de novo purine synthesis on which lymphocytes are dependent. Two oral forms are available, the mofetil ester and enteric-coated MPA which protects MPA from acid. The primary toxicities of MPA are gastrointestinal side effects and leukopenia. MMF is typically used in combination with a calcineurin inhibitor with or without prednisone. In adults, the oral dosage range for MMF is 1000–2000 mg/day in two divided doses and for enteric-coated MPA 720-1440 mg/d. Unlike calcineurin inhibitors, blood levels do not correlate with efficacy or toxicity . Animals exhibited developmental toxicity, malformations, intrauterine death, or intrauterine growth retardation at MMF doses which appear to be within recommended clinical doses based on body surface area. Regarding human exposures, post-marketing surveillance and NTPR data demonstrated that maternal exposure to MPA during pregnancy carries an increased risk of spontaneous abortion and a specific pattern and increased incidence of malformations . The specific pattern included microtia, an ear deformity, and other facial malformations, such as cleft lip and palate. The recommendation is that females of childbearing potential use contraception while taking MPA and that the medication should be discontinued 6 weeks prior to conceiving. These risks have not been noted in pregnancies fathered by transplant recipients taking MPA.

When a patient taking MPA approaches her health-care provider to plan a pregnancy, options, such as temporarily replacing the MPA with azathioprine or sirolimus in conjunction with adding or increasing prednisone, should be considered, attempting to balance the risks to the transplant and the risks to the pregnancy. Questions remain unanswered such as whether the risks to the fetus are dose related, what to do in the setting of an unplanned pregnancy, and if MPA can be resumed after fetal organogenesis is complete.

Sirolimus (Category C)

Sirolimus is a macrolide antibiotic with a novel mechanism of action. It has no effect on calcineurin activity, but inhibits cytokine driven T-cell proliferation, thus preventing the progression from the G1 to the S-phase of the cell cycle. This is at least two steps later in the cell activation/proliferation cascade than the calcineurin-dependent steps. Sirolimus is usually used in conjunction with a calcineurin inhibitor. Typical dosing for renal recipients is a single daily dose of 1–5 mg adjusted for trough levels. In animal studies, decreased fetal weights and delayed ossification of skeletal structures were reported, but no teratogenicity was noted. When administered in combination with cyclosporine to pregnant animals, there was increased fetal mortality, increased numbers of resorptions, and decreased numbers of live fetuses, suggesting increased toxicity in conjunction with calcineurin inhibition . Regarding human exposure, NTPR data have not demonstrated a pattern of birth defects; however, data are limited .

Everolimus (Category C)

Everolimus, a structural analog of sirolimus, has a higher oral availability, a shorter half-life, and is associated with faster achievement of stable blood levels .

Daily everolimus administration to pregnant rats, at 0.1 mg/kg before mating and through organogenesis, resulted in an increased preimplantation loss and in early fetal resorptions. The area under the curve (AUC) in rats at this dose was approximately one-third of that in humans administered the starting clinical dose (0.75 mg twice daily). Everolimus administered daily at 0.8 mg/kg to pregnant rabbits resulted in increased late fetal resorptions, which is slightly less than the AUCs in humans given the starting clinical dose . There are a few reports of pregnancy exposure to everolimus with no malformations reported .